We and other investigators have shown that there are kindreds who have a nonrandom recurrence of aneuploid offspring. Based on these observations one can postulate that humans are similar to other eukaryotes in that genetic factors cause some cases of nondisjunction. We plan to formally test this hypothesis by estimating the proportion of variation in human aneuploidy that is attributable to genetic and/or environmental factors. This will be done by scoring the levels of aneuploidy in human sperm from identical and fraternal twins using a multi-color fluorescence in situ hybridization (FISH) technique. A total of 100 twin pairs (50 monozygotic pairs and 50 dizygotic pairs) will be studied. Levels of aneuploidy seen for each of the 24 chromosomes in sperm from each of the 200 twins will be scored. The extent to which individual differences in aneuploidy are determined by additive genetic, common environmental, and specific environment effects will be estimated using a method of robust variance component estimation (implemented in the FISHER quantitative genetics package). The sperm aneuploidy frequencies will also be used to compare differences between: (1) males; (2) chromosomes; (3) chromosomes within males; (4) chromosomes within males between ejaculates; and (5) levels of sperm morphological abnormalities. Males identified as having significantly high levels of aneuploidy will be further studied, along with their co-twins (who may be concordant or discordant for high aneuploidy levels) and controls, to test if differences in alpha-satellite DNA sequences, centromere associated proteins (CENPs), or premature centromere division are correlated with the elevated aneuploidy frequencies. Also, for this subset of twins the level of aneuploidy in gametes (sperm) will be compared to levels seen in somatic cells (lymphocytes). This latter comparison will provide information about the utility of somatic cells in screening tests to estimate the effects of environmental or genetic agents on gametic aneuploidy. Collectively, the results of this study will not only allow us to provide the first quantitative estimate of the role of genetic factors in the incidence of aneuploidy, but could also provide important insight for designing human mutagen screening tests, and providing genetic counseling to families having a child with an aneuploid condition.